title: Non-transmissible Sendai virus encoding granulocyte macrophage colony-stimulating factor is a novel and potent vector system for producing autologous tumor vaccines.
abstract: The recent clinical application of granulocyte macrophage colony-stimulating factor (GM-CSF)-transduced autologous tumor vaccines revealed substantial antitumor activity and valuable clinical results. However, for these vaccines to be optimally effective, the antitumor efficacies must be improved. Recently, Sendai virus (SeV) vectors, which are cytoplasmic RNA vectors, have emerged as safe vectors with high gene transduction. In the current study, the in vivo therapeutic antitumor efficacies of irradiated GM-CSF-transduced mouse renal cell carcinoma (RENCA) vaccine cells mediated by either fusion gene-deleted non-transmissible SeV encoding mouse GM-CSF (SeV/dF/G) or adenovirus (E1, E3 deleted serotype 5 adenovirus) encoding mouse GM-CSF (AdV/G) (respectively described as irRC/SeV/GM or irRC/AdV/GM) were compared in RENCA-bearing mice. The results showed that the antitumor effect was equivalent between irRC/SeV/GM and irRC/AdV/GM cells, even though the former produced less GM-CSF in vitro. The cell numbers of activated (CD80(+), CD86(+), CD80( (+) )CD86(+)) dendritic cells in lymph nodes from mice treated with irRC/AdV/GM or irRC/SeV/GM cells were increased significantly compared with those of mice treated with the respective controls, at both the earlier and later phases. In an in vitro cytotoxicity assay, splenocytes harvested from mice treated with both irRC/SeV/GM and irRC/AdV/GM cells showed tumor-specific responses against RENCA cells. The restimulated splenocytes harvested from mice treated with irRC/SeV/GM or irRC/AdV/GM cells produced significantly higher levels of interleukin-2, interleukin-4, and interferon-gamma compared with their respective controls (P < 0.05). Furthermore, vaccination with irRC/AdV/GM or irRC/SeV/GM cells induced significantly enhanced recruitment of the cytolytic effectors of CD107a(+)CD8(+) T cells and CD107a(+) natural killer cells into tumors compared with those induced by their respective controls (P < 0.05). Taken together, our results suggest that the SeV/dF/G vector is a potential candidate for the production of effective autologous GM-CSF-transduced tumor vaccines in clinical cancer immune gene therapy.
authors.affiliation: Department of Advanced Cell and Molecular Therapy, Division of Molecular and Clinical Genetics, Medical Institute of Bioregulation, Kyushu University Hospital, Kyushu University, Fukuoka, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Inoue
authors.forename: Mutsunori
authors.initials: M
authors.lastname: Iga
authors.forename: Haruka
authors.initials: H
authors.lastname: Nabeta
authors.forename: Tomoko
authors.initials: T
authors.lastname: Yokoo
authors.forename: Yoko
authors.initials: Y
authors.lastname: Suehiro
authors.forename: Shinji
authors.initials: S
authors.lastname: Okano
authors.forename: Makoto
authors.initials: M
authors.lastname: Inoue
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kinoh
authors.forename: Toyomasa
authors.initials: T
authors.lastname: Katagiri
authors.forename: Koichi
authors.initials: K
authors.lastname: Takayama
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Yonemitsu
authors.forename: Mamoru
authors.initials: M
authors.lastname: Hasegawa
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Nakanishi
authors.forename: Kenzaburo
authors.initials: K
authors.lastname: Tani
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000276:immunology; D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D045744:Cell Line, Tumor; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D029082:Sendai virus / Q000235:genetics*; D014161:Transduction, Genetic
chemical_list: D019496:Cancer Vaccines; D016178:Granulocyte-Macrophage Colony-Stimulating Factor